U.S. patent number 4,564,613 [Application Number 06/651,001] was granted by the patent office on 1986-01-14 for pyridoindole derivatives, compositions and use.
This patent grant is currently assigned to Troponwerke GmbH & Co.. Invention is credited to Karl-Heinz Boltze, Margaret A. Davies, Bodo Junge, Teunis Schuurman, Jorg Traber.
United States Patent |
4,564,613 |
Boltze , et al. |
January 14, 1986 |
**Please see images for:
( Certificate of Correction ) ** |
Pyridoindole derivatives, compositions and use
Abstract
Pyridoindoles of the formula ##STR1## in which R.sub.1
represents hydrogen or C.sub.1 -C.sub.4 -alkyl, which is optionally
substituted by the radical ##STR2## R.sub.2 and R.sub.3 represent H
or form a bond, or R.sub.1 and R.sub.2 together represent O,
--O--CH.sub.2 --CH.sub.2 --O-- or --S--CH.sub.2 --CH.sub.2 --S--,
R.sub.4 represents H or the ##STR3## or R.sub.3 and R.sub.4
represent O, or R.sub.1 and R.sub.4 are members of an N-containing
six-membered ring and R.sub.8 and R.sub.9 represent H or C.sub.1
-C.sub.4 -alkyl, or optionally form, with the N atom, a
heterocyclic 5-membered or 6-membered ring, which can optionally
also contain a further hetero-atom from the series comprising N, O
or S, R.sub.5 represents H, C.sub.1 -C.sub.4 -alkyl or the group
##STR4## or R.sub.5 and R.sub.3 form a bond, and R.sub.10 and
R.sub.11 represent C.sub.1 -C.sub.4 -alkyl or are members of an
N-containing 5-membered or 6-membered ring, R.sub.6 represents H or
C.sub.1 -C.sub.4 -alkyl and R.sub.7 represents halogen, or acid
addition salts thereof, which are active on the central nervous
system. Novel intermediates are also shown.
Inventors: |
Boltze; Karl-Heinz (Borod,
DE), Davies; Margaret A. (Cologne, DE),
Junge; Bodo (Wuppertal, DE), Schuurman; Teunis
(Overath, DE), Traber; Jorg (Lohmar, DE) |
Assignee: |
Troponwerke GmbH & Co.
(Cologne, DE)
|
Family
ID: |
6209594 |
Appl.
No.: |
06/651,001 |
Filed: |
September 14, 1984 |
Foreign Application Priority Data
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|
|
|
|
Sep 21, 1983 [DE] |
|
|
3333994 |
|
Current U.S.
Class: |
514/232.8;
514/278; 514/292; 544/61; 544/70; 544/126; 544/361; 546/64; 546/86;
514/253.03; 514/232.5; 514/287; 544/58.6; 544/78; 544/357; 546/15;
546/84; 546/87 |
Current CPC
Class: |
A61P
25/00 (20180101); C07D 471/14 (20130101); A61P
25/20 (20180101); C07D 471/04 (20130101); C07D
217/04 (20130101); A61P 25/24 (20180101); A61P
25/26 (20180101) |
Current International
Class: |
C07D
471/00 (20060101); C07D 217/00 (20060101); C07D
217/04 (20060101); C07D 471/04 (20060101); C07D
471/20 (20060101); C07D 471/14 (20060101); A61K
031/44 (); A61K 031/535 (); C07D 471/14 (); C07D
471/04 () |
Field of
Search: |
;544/58.6,61,70,78,126,357,361 ;546/15,64,84,86,87
;514/222,227,230,238,239,252,278,287,292 |
Other References
R C. Elderfield, "Heterocyclic Compounds", vol. 3, 1952, John Wiley
& Sons, N.Y., pp. 208, 209. .
Chemical Abstracts, vol. 86, No. 25, Jun. 20, 1977, p. 611, col. 2,
Abstract No. 189,902k, "Pyridoindole Derivatives", R. Tachikawa.
.
Chemical Abstracts, vol. 84, No. 11, Mar. 15, 1976, p. 440, col. 1,
Abstract No. 74,140b, "Bischler-Napieralski Reactions . . . ", S.
Naruto..
|
Primary Examiner: Ramsuer; Robert W.
Attorney, Agent or Firm: Sprung, Horn, Kramer &
Woods
Claims
We claim:
1. A pyridoindole of the formula ##STR69## in which R.sub.1
represents hydrogen or C.sub.1 -C.sub.4 -alkyl, which is optionally
substituted by the radical ##STR70## R.sub.2 and R.sub.3 represent
H or form a bond, or R.sub.1 and R.sub.2 together represent O,
--O--CH.sub.2 --CH.sub.2 --O-- or --S--CH.sub.2 --CH.sub.2
--S--,
R.sub.4 represents H or the ##STR71## or R.sub.3 and R.sub.4
represent O, or
R.sub.1 and R.sub.4 are members of an N-containing six-membered
ring and
R.sub.8 and R.sub.9 represent H or C.sub.1 -C.sub.4 -alkyl, or
optionally form, with the N atom, a heterocyclic 5-membered or
6-membered ring, which can optionally also contain a further
hetero-atom from the series comprising N, O or S,
R.sub.5 represents H, C.sub.1 -C.sub.4 -alkyl or the group
##STR72## or R.sub.5 and R.sub.3 form a bond, and
R.sub.10 and R.sub.11 represent C.sub.1 -C.sub.4 -alkyl or are
members of an N-containing 5-membered or 6-membered ring,
R.sub.6 represents H or C.sub.1 -C.sub.4 -alkyl and
R.sub.7 represents H or halogen or an acid addition salt
thereof.
2. A compound or salt according to claim 1,
in which
R.sub.1 represents H or C.sub.1 -C.sub.3 -alkyl, which is
substituted by the radical ##STR73## wherein R.sub.8 and R.sub.9
independently of one another represent
H or C.sub.1 -C.sub.4 -alkyl or, together with the N atom, form a
piperidine, pyrrolidone, morpholine or piperazine ring,
R.sub.4 and R.sub.5 represent H,
R.sub.2 and R.sub.3 represent H or form a bond,
R.sub.6 represents CH.sub.3 and
R.sub.7 represents H or F.
3. A compound or salt according to claim 1,
in which
R.sub.1, R.sub.4 and R.sub.5 represent H,
R.sub.2 and R.sub.3 represent H or form a bond,
R.sub.6 represents CH.sub.3 and
R.sub.7 represents F.
4. A compound according to claim 1, wherein such compound is
8-methyl-6-(4-fluorophenyl)-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole
of the formula ##STR74## or an acid addition salt thereof.
5. A compound according to claim 1, wherein such compound is
8-methyl-6-(4-fluorophenyl)-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3-g]indole
of the formula ##STR75## or an acid addition salt thereof.
6. A compound according to claim 1, wherein such compound is
3-(4-morpholinylmethyl)-8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3
-g]indole of the formula ##STR76## or an acid addition salt
thereof.
7. A compound according to claim 1, wherein such compound is
3-(isopropylaminoethyl)-8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3
-g]indole of the formula ##STR77## or an acid addition salt
thereof.
8. A composition active on the central nervous system comprising a
central nervous system-output modifying effective amount of a
compound or salt according to claim 1 in admixture with a
diluent.
9. A method of modifying the output of the central nervous system
which comprises administering to a patient in need thereof a
central nervous system-output modifying effective amount of a
compound or salt according to claim 1.
10. The method according to claim 10, wherein such compound is
8-methyl-6-(4-fluorophenyl)-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole,
8-methyl-6-(4-fluorophenyl)-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3-g]indole,
3-(4-morpholinylmethyl)-8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-
g]indole or
3-(isopropylaminoethyl)-8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-
g]indole, or an acid addition salt thereof.
Description
The present invention relates to new pyridoindole derivatives and
acid addition salts thereof, processes for their preparation and
their use in combating diseases, in particular their use for the
treatment of diseases of the central nervous system.
The invention relates to pyrodoindoles of the general formula I
##STR5## in which R.sub.1 represents hydrogen or straight-chain or
branched C.sub.1 -C.sub.4 -alkyl, which is optionally substituted
by the radical ##STR6## R.sub.2 and R.sub.3 represent H or form a
bond, or R.sub.1 and R.sub.2 together represent oxygen,
--O--CH.sub.2 --CH.sub.2 --O-- or --S--CH.sub.2 --CH.sub.2
--S--,
R.sub.4 represents H or a ##STR7## or R.sub.3 and R.sub.4 represent
oxygen, or
R.sub.1 and R.sub.4 are members of an N-containing six-membered
ring and
R.sub.8 and R.sub.9 represent H or C.sub.1 -C.sub.4 -alkyl, or
optionally form, with the N atom, a heterocyclic 5-membered or
6-membered ring, which can optionally also contain a further
hetero-atom from the series comprising N, O or S,
R.sub.5 represents H, C.sub.1 -C.sub.4 -alkyl or the group ##STR8##
or R.sub.5 and R.sub.3 form a bond, and
R.sub.10 and R.sub.11 represent C.sub.1 -C.sub.4 -alkyl or are
members of an N-containing 5-membered or 6-membered ring,
R.sub.6 represents H or C.sub.1 -C.sub.4 -alkyl and
R.sub.7 represents H or halogen, in particular F, Cl or Br.
The invention extends to the racemic mixture as well as to the
individual enantiomers of the compounds of the formula I. The
enantiomers can be prepared from the racemates by conventional
methods, for example by fractional crystallization of
diastereomeric salts with optically active acids or by column
chromatography on optically active carrier materials.
It has furthermore been found that the compounds of the general
formula I are obtained when compounds of the general formula II
##STR9## in which R.sub.6 and R.sub.7 have the abovementioned
meaning, are subjected to a double-cyclization reaction in the
presence of a dehydrating agent. Isatins of the general formula Ia
are thus obtained. ##STR10##
Compounds of the formula Ia are also obtained when compounds of the
formula III ##STR11## in which R.sub.6 and R.sub.7 have the
abovementioned meaning, are cyclized in the presence of a
dehydrating agent.
Starting from the isatins of the formula Ia, other compounds of the
formula I can be prepared. Thus, reduction of the isatins Ia with
complex metal hydrides gives the indoles Ib ##STR12## which can in
turn be further reduced to the dihydroindoles Ic ##STR13## Reaction
of the indoles Ib with Mannich reagents (n=1) or with oxalyl
chloride (n=2) and then with a primary or secondary amine of the
formula IV ##STR14## in which
R.sub.8 and R.sub.9 have the abovementioned meaning, with
subsequent reduction leads to compounds of the formula Id with
basic alkyl radicals in the indole ring. ##STR15##
Further reaction of the compounds of the formula Id (n=2) with
formaldehyde gives .beta.-carbolines of the formula Ie.
##STR16##
Compounds of the formula If are obtained from the isatins of the
formula Ia when the keto function is ketalized with ethylene
glycol, the acid amide function is sulphurized with Lawesson's
reagent and the thioamide function is then converted into an
amidine function with primary or secondary amines of the formula
IV. ##STR17## are obtained from compounds of the formula Ic by
reductive alkylation with C.sub.1 -C.sub.4 -aldehydes and
NaCNBH.sub.3.
Reaction of compounds of the formula Ic with acid amides of the
formula V ##STR18## in which
R.sub.10 and R.sub.11 have the abovementioned meaning, and
POCl.sub.3 gives the compounds of the formula Ih. ##STR19##
The active compounds of the general formula I according to the
invention exhibit a marked effect on the central nervous system.
They display anxiolytic and nootropic actions, and in particular
also antidepressive actions. They are therefore particularly
suitable for the treatment of depressive conditions and thus
represent an enrichment of the range of medicaments.
Preferred compounds of the formula I are those in which
R.sub.1 represents H or C.sub.1 -C.sub.3 -alkyl, which is
substituted by the radical ##STR20## wherein R.sub.8 and R.sub.9
independently of one another represent H or C.sub.1 -C.sub.4 -alkyl
or, together with the N atom, form a piperidine, pyrrolidine,
morpholine or piperazine ring,
R.sub.4 represents H,
R.sub.2 and R.sub.3 represent H or form a bond,
R.sub.5 represents H,
R.sub.6 represents CH.sub.3 and
R.sub.7 represents H or F.
Particularly preferred compounds of the formula I are those
in which
R.sub.1 and R.sub.4 represent H,
R.sub.2 and R.sub.3 represent H or form a bond,
R.sub.5 represents H,
R.sub.6 represents CH.sub.3 and
R.sub.7 represents F.
The preparation of compounds of the formula Ia is illustrated, by
way of example, by the following equation: ##STR21##
Another process for the preparation of compounds of the formula Ia
is illustrated, by way of example, by the following equation:
##STR22##
The two equations below illustrate, by way of example, the
preparation of compounds of the formulae Ib and Ic: ##STR23##
Starting from the compounds Ic, the compounds Ig and Ih are
obtained as illustrated by way of example, by the following
equations: ##STR24##
The two following examples illustrate the preparation of the
compounds of the formula Id: ##STR25##
Carbolines of the formula Ie are obtained by the reaction route
illustrated by the following example: ##STR26##
The following equation describes, by way of example, the
preparation of amidines of the formula If: ##STR27##
The reaction of the oximes II to give the isatins Ia is carried out
in a strong dehydrating acid as the solvent. Suitable acids of this
type are concentrated sulphuric acid or polyphosphoric acid. The
reaction can be carried out at temperatures between about
10.degree. C. and 120.degree. C. The reaction is preferably carried
out between 30.degree. C. and 80.degree. C., in particular between
40.degree. C. and 50.degree. C. The reaction times vary between a
few minutes and some hours, depending on the temperature. If the
reaction is carried out between 40.degree. C. and 50.degree. C.,
the reaction time is about 1 hour.
The reaction of the oximes III to give the isatins Ia is also
carried out under the same reaction conditions.
The reduction of the isatins Ia to the indoles Ib is preferably
carried out with complex metal hydrides, in particular with
LiAlH.sub.4. Solvents which are used are inert aprotic solvents, in
particular ethers, such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, diglyme or mixtures of these solvents. The
reaction is carried out at temperatures between room temperature
and the boiling point of the solvent, in particular at room
temperature.
The reduction of the indoles Ib to the dihydroindoles Ic is
preferably carried out with boron hydride compounds. Aminoborane
complexes or NaBH.sub.4 or NaCNBH.sub.3 in organic acids, such as
acetic acid or trifluoroacetic acid, are preferably used. The
solvents used are mixtures of aqueous mineral acids, for example
aqueous hydrochloric acid, with organic solvents, such as dioxane,
tetrahydrofuran or ethanol, or organic carboxylic acids, such as
acetic acid or trifluoroacetic acid. The reaction is carried out at
temperatures between room temperature and the boiling point of the
solvent. Mixtures of organic solvents with aqueous mineral acids or
organic acids, or aqueous organic acids are used as the solvent for
the preparation of the Mannich bases Id (n=1) from the indoles Ib.
The reaction is preferably carried out in aqueous acetic acid. The
reaction is carried out between 0.degree. C. and 100.degree. C.,
preferably at room temperature.
The indoles Ib are reacted with oxalyl chloride to prepare the
compounds Id (n=2) in an inert organic solvent in the presence of
an acid-binding agent.
Preferred solvents which may be mentioned are: dioxane,
tetrahydrofuran, toluene, chlorobenzene, methylene chloride and
dichloroethane. The acid-binding agents used are inorganic salts,
such as potassium carbonate or sodium bicarbonate, or tertiary
organic bases, such as triethylamine or diaminobutyric acid. The
use of dioxane as the solvent and K.sub.2 CO.sub.3 as the
acid-binding agent is particularly preferred.
The reaction is carried out at temperatures between -20.degree. C.
and 60.degree. C., preferably at about 0.degree. C. Further
reaction of the intermediates thus obtained with amines of the
formula IV is carried out under the same reaction conditions as
described above, preferably in dioxane as the solvent and with
K.sub.2 CO.sub.3 as the auxiliary base.
The reaction of these intermediates to compounds of the formula Id
(n=2) is preferably carried out with complex metal hydrides, in
particular with LiAlH.sub.4. The solvents used are inert aprotic
solvents, in particular ethers, such as diethyl ether,
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme or mixtures
of these solvents. Absolute tetrahydrofuran is particularly
preferably used as the solvent. The reaction is carried out at
temperatures between room temperature and the boiling point of the
solvent, particularly preferably at the boiling point of the
solvent.
The reaction of compounds of the formula Id (n=2, R.sub.8 =H) with
formaldehyde to give .beta.-carbolines of the formula Ie is
preferably carried out in aqueous mineral acids; the use of aqueous
hydrochloric acid is particularly preferred. The reaction is
carried out between 0.degree. and 80.degree. C., preferably at room
temperature.
The reaction of the isatins Ia with ethylene glycol to prepare
compounds If is carried out in an inert organic solvent by boiling
in the presence of an acid catalyst, using a water separator.
Solvents which may be mentioned are: dichloroethane, toluene and
chlorobenzene. The use of dichloroethane as the solvent and
p-toluenesulphonic acid as the catalyst is preferred.
The sulphurization of the intermediates thus obtained is carried
out with Lawesson's reagent ##STR28## or P.sub.2 S.sub.5 in an
inert organic solvent. Toluene, xylene, dimethoxyethane,
tetrahydrofuran or dioxane is used as such a solvent. The use of
toluene as the solvent is particularly preferred. The reaction is
preferably carried out at the boiling point of the solvent.
The reaction of the thioamides thus obtained with amines of the
formula IV to give the amidines of the formula If can be carried
out with or without a solvent. An excess of amine of the formula IV
is preferably used as the solvent. The reaction is carried out at
temperatures between 50.degree. C. and 150.degree. C., preferably
at temperatures between 80.degree. C. and 120.degree. C.
Compounds of the formula Ig (R.sub.5 =C.sub.1 -C.sub.4 -alkyl) are
prepared by alkylation of the amines Ic. Reductive alkylation of
the amines Ic with aldehydes and ketones in the presence of a
hydrogen donor is preferred. Polar organic solvents or mixtures
thereof with water are used as the solvent. The use of alcohols as
the solvent, in particular the use of methanol, is preferred. The
reaction is carried out in a pH range between 3 and 8, preferably
in a pH range between 5 and 6. This pH value is preferably
established by addition of an organic acid, in particular by
addition of acetic acid. The reaction is carried out at
temperatures between 0.degree. C. and the boiling point of the
solvent; the reaction is preferably carried out at room
temperature.
Reaction of the amines Ic with acid amides of the formula V in the
presence of POCl.sub.3 to give amidines of the formula Ih is
carried out in inert organic solvents. Toluene, xylene,
dichloroethane, chloroform, tetrahydrofuran and dioxane may be
mentioned. Toluene is preferably used. The reaction of the acid
amide with POCl.sub.3 is carried out at temperatures between
0.degree. and 80.degree. C. The reaction is preferably carried out
at room temperature. The reaction of the amine with the activated
acid amide is carried out at temperatures between room temperature
and the boiling point of the solvent. The reaction is preferably
carried out between 70.degree. C. and 90.degree. C.
The starting substances of the formula II are new. They can be
prepared from the amines of the formula VI ##STR29## by reaction
with chloral hydrate and hydroxylamine. (Sandmeyer isatin synthesis
(Krauch, Kunz; Reaktionen der organischen Chemie (Reactions of
Organic Chemistry), Dr. Alfred Huthig, Verlag Heidelberg, 5th
edition).)
Some of the amines are known. Where they are new, they can be
prepared by processes which are known from the literature, such as
those described in German Patent Application DE-PS No.
1,670,694.
The starting substances of the formula III are new. They can be
prepared from amines of the formula VII ##STR30## (Sandmeyer isatin
synthesis).
Some of the amines of the formula VII are known from German Patent
Application DE-PS No. 1,670,694. New compounds of the formula VII
can be prepared analogously to the compounds described therein.
The present invention includes pharmaceutical formulations which,
in addition to non-toxic, inert pharmaceutically suitable
excipients, contain one or more compounds of the above general
formula I, or which consist of one or more compounds of the above
formula, as well as processes for the preparation of these
formulations.
The present invention also includes pharmaceutical formulations in
dosage units. This means that the formulations are in the form of
individual parts, for example tablets, dragees, capsules, pills,
suppositories and ampules of which the content of active compound
corresponds to a fraction or a multiple of an individual dose. The
dosage units can contain, for example, 1, 2, 3 or 4 individual
doses or 1/2, 1/3 or 1/4 of an individual dose. An individual dose
preferably contains the amount of active compound which is given in
one administration and which usually corresponds to a whole, a
half, a third or a quarter of a daily dose.
By non-toxic, inert pharmaceutically suitable excipients there are
to be understood solid, semi-solid or liquid diluents, fillers and
formulation auxiliaries of every kind.
Tablets, dragees, capsules, pills, granules, suppositories,
solutions, suspensions and emulsions may be mentioned as preferred
pharmaceutical formulations.
Tablets, dragrees, capsules, pills and granules can contain the
active compound or compounds alongside the customary excipients,
such as (a) fillers and extenders, for example starches, lactose,
sucrose, glucose, mannitol and silica, (b) binders, for example
carboxymethylcellulose, alginates, gelatine and
polyvinylpyrrolidone, (c) humectants, for example glycerol, (d)
disintegrating agents, for example agar-agar, calcium carbonate and
sodium bicarbonate, (e) solution retarders, for example paraffin,
and (f) resorption accelerators, for example quaternary ammonium
compounds, (g) wetting agents, for example cetyl alcohol and
glycerol monostearate, (h) adsorbents, for example kaolin and
bentonite, and (i) lubricants, for example talc stearate, calcium
stearate and magnesium stearate and solid polyethylene glycols, or
mixtures of the compounds listed under (a) to (i).
The tablets, dragees, capsules, pills and granules can be provided
with the customary coatings and shells, optionally containing
opacifying agents, and can also be of such composition that they
release the active compound or compounds only, or preferentially,
in a certain part of the intestinal tract, optionally in a delayed
manner, examples of embedding compositions which can be used being
polymeric substances and waxes.
The active compound or compounds, optionally together with one or
more of the abovementioned excipients, can also be in a
micro-encapsulated form.
Suppositories can contain, in addition to the active compound or
compounds, the customary water-soluble or water-insoluble
excipients, for example polyethylene glycols, fats, for example
cacao fat, and higher esters (for example C.sub.14 -alcohol with
C.sub.16 -fatty acid), or mixtures of these substances.
Solutions and emulsions can contain, in addition to the active
compound or compounds, the customary excipients, such as solvents,
solubilizing agents and emulsifiers, for example water, ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene-glycol,
dimethylformamide, oils, especially cottonseed oil, groundnut oil,
corn germ oil, olive oil, castor oil and sesame oil, glycerol,
glycerol-formal, tetrahydrofurfuryl alcohol, polyethylene glycols
and fatty acid esters of sorbitan, or mixtures of these
substances.
For parenteral administration, the solutions and emulsions can also
be in a sterile form which is isotonic with blood.
Suspensions can contain, in addition to the active compound or
compounds, the customary excipients, such as liquid diluents, for
example water, ethyl alcohol or propylene glycol, suspending
agents, for example ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol esters and sorbitan esters,
micro-crystalline cellulose, aluminum methane hydroxide, bentonite,
agar-agar and tragacanth, or mixtures of these substances.
The formulation forms mentioned can also contain colorants,
preservatives and additives which improve the odor and flavor for
example peppermint oil and eucalyptus oil, and sweeteners, for
example saccharine.
The therapeutically active compounds should be present in the
abovementioned pharmaceutical formulations in a concentration of
about 0.1 to 99.5, preferably of about 0.5 to 95, % by weight of
the total mixture.
The abovementioned pharmaceutial formulations can also contain
other pharmaceutically active compounds in addition to active
compounds of the above formula.
The abovementioned pharmaceutical formulations are prepared in the
customary manner according to known methods, for example by mixing
the active compound or compounds with the excipient or
excipients.
The present invention also includes the use of the compounds of the
above formula and the use of pharmaceutical formulations which
contain one or more compounds of the abovementioned formula, in
human and veterinary medicine, for the prevention, alleviation
and/or cure of the abovementioned diseases.
The active compounds or the pharmaceutical formulations can be
administered orally, parenterally, intraperitoneally and/or
rectally, preferably orally, if appropriate in a formulation which
is resistant to gastric juice.
In general, it has proved advantageous to administer the active
compound or compounds orally in amounts of about 0.01 to about 100,
preferably 0.1 to 10, mg/kg of body weight every 24 hours,
distributed over 1 to 6 administrations, and in particular before
and/or during and/or after meals. An individual dose contains the
active compound or active compounds in amounts of, preferably,
about 0.1 to about 5 mg/kg of body weight. However, it may be
necessary to deviate from the dosages mentioned, and in particular
to do so as a function of the nature and body weight of the subject
to be treated, the nature and severity of the disease, the nature
of the formulation and of the administration of the medicament and
the period or interval within which administration takes place.
Thus it can in some cases suffice to manage with less than the
abovementioned amount of active compound, but in other cases the
abovementioned amount of active compound must be exceeded. The
particular optimum dosage required and the type of administration
of the active compounds can easily be determined by anyone skilled
in the art on the basis of his expert knowledge.
Some test results for the new compounds of the general formula I
which were tested for anxiolytic, nootropic and antidepressive
properties are given below. The pilot tests used were inhibition of
footshock induced aggression (Tedeschi et al., J. Pharmacol. Exp.
Ther. 129, p. 28-34, 1954), for the anxiolytic action and the
antitetrabenazine test (J. L. Howard et al., in: Antidepressants:
Neurochemical, Behavioral and Clinical Perspectives, edited by S.
J. Enna et al., Raven Press N.Y., pages 107-120, 1981) and
amphetamine potentiation test (J. L. Howard et al., in:
Antidepressants: Neurochemical, Behavioral and Clinical
Perspectives, edited by S. J. Enna et al., Raven Press N.Y., pages
107-120, 1981) for the antidepressive action.
The following values were found, for example, for the
antidepressive actions of the substances according to the
invention:
(1) Tetrabenazine antagonism
Substances having an antidepressive action antagonize the ptosis in
mice induced by tetrabenazine. The ED.sub.50 value indicates the
dose at which the ptosis induced by 20 mg/kg of tetrabenazine
intraperitoneally is reduced to 50%. Examples which may be
mentioned here are:
______________________________________ ED.sub.50 (mg/kg intra-
Compound peritoneally) ______________________________________ 1 a
(as the free base) 1.0 1 b (as the free base) 2.0 2 a (as the
maleate salt) 0.3 2 b (as the maleate salt) 0.2 3 a (as the
hydrochloride) 0.1 3 b (as the hydrochloride) 0.01 4 (as the
hydrochloride) 0.01 7 a (as the hydrochloride) 0.1 7 b (as the
hydrochloride) 0.1 6 c (as the hydrochloride) 2.0
______________________________________
(2) Amphetamine potentiation
Substances having an antidepressive action potentiate the
amphetamine-induced stereotype behavior in rats.
The ED.sub.50 value given is the dose at which the
amphetamine-induced behavior is intensified by 50% following
intravenous administration of 2 mg/kg of DL-amphetamine sulphate.
Examples which may be mentioned here are:
______________________________________ ED.sub.50 (mg/kg intra-
Compound peritoneally) ______________________________________ 2 a
(as the maleate salt) 2.4 2 b (as the maleate salt) 3.9 3 a (as the
hydrochloride) 1.2 3 b (as the hydrochloride) 2.2
______________________________________
The present invention may be illustrated in more detail by the
following examples.
EXAMPLE 1
8-Methyl-6-(4-fluorophenyl)-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole-2,3-d
ione ##STR31##
A solution of 27 g (0.0781 mol) of
2-methyl-(2-(hydroxyiminoacetylamino)benzyl)amino-1-(4-fluorophenyl)-ethan
ol in 35 ml of CH.sub.2 Cl.sub.2 is added dropwise, with stirring
and in the absence of moisture, to 78 ml (1.37 mols) of
concentrated H.sub.2 SO.sub.4, which is warmed to 35.degree. C.,
and the mixture is subsequently stirred at 45.degree. C. for 1
hour. The reaction solution is poured onto 500 g of ice and brought
to pH 6.8 at 0.degree. C. with 25% strength NaOH. The precipitate
is filtered off with suction, washed with H.sub.2 O and dried in a
desiccator at 60.degree. C. over P.sub.2 O.sub.5 under a water pump
vacuum.
Yield: 22.1 g (91%) of yellow-colored substance; melting point
(micro-Kofler): 197.degree.-200.degree. C., with decomposition
The following compound was prepared analogously:
8-Methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]-indole-2,3-dione
##STR32##
Yield: 90% of theory; melting point (Mettler FP61): 214.7.degree.
C.
Preparation of the starting substances
2-Methyl(2-(hydroxyiminoacetylamino)benzyl)amino)-1-phenylethanol
##STR33##
189.9 g (1.146 mols) of chloral hydrate are dissolved in 2.6 liters
of H.sub.2 O, with stirring, and a solution of 306 g of
2-methyl(2-aminobenzyl)amino-1-phenylethanol in 666 ml of H.sub.2 O
is added at room temperature. After 5 minutes, 1280 g of Na.sub.2
SO.sub.4 and a solution of 229 g (3.297 mols) of hydroxylamine
hydrochloride in 1.08 liters of H.sub.2 O are added. The mixture is
then warmed to an internal temperature of 106.degree. C. in the
course of 40 minutes. The reaction temperature is kept at
106.degree. C. for 2 minutes and is then brought to room
temperature by rapid cooling with ice/H.sub.2 O. MeOH is added to
the reaction mixture until the organic substances have dissolved. A
pH value of 7.8 is established with 25% strength NaOH and the
solvent is stripped off on a rotary evaporator. The aqueous phase
is extracted with ethyl acetate, the organic phase is dried over
Na.sub.2 SO.sub.4 and the solvent is evaporated off on a rotary
evaporator. The residue is freed from traces of solvent under an
oil pump vacuum and is then dried in a desiccator over P.sub.2
O.sub.5.
Yield: 317 g (91%)
The following compound was obtained by an analogous route:
2-(Methyl-(2-hydroxyiminoacetylamino)benzyl)amino)-1-(4-fluorophenyl)ethano
##STR34##
The crude product was chromatographed on silica gel 60 using ethyl
acetate as the eluent.
Yield: 76% of theory.
2-(Methyl-(2-aminobenzyl)amino)-1-(4-fluorophenyl)ethanol
##STR35##
A solution of 124.5 g (0.409 mol) of
2-methyl-(2-nitrobenzyl)-amino-1-(4-fluorophenyl)ethanol in 150 ml
of ethanol and 500 ml of ethyl acetate is hydrogenated with 1 g of
PtO.sub.2 at room temperature under atmospheric pressure until 3
molar equivalents of H.sub.2 have been taken up. The catalyst is
filtered off, the filtrate is evaporated on a rotary evaporator and
the residue is dissolved in 450 ml of CH.sub.2 Cl.sub.2. The
CH.sub.2 Cl.sub.2 phase is washed 3 times with 200 ml of H.sub.2 O
each time and dried over Na.sub.2 SO.sub.4. After filtration,
HCl/diethyl ether is added. The salt which has precipitated is
filtered off with suction, washed with diethyl ether and dried in a
desiccator over NaOH at 60.degree. C. under a water pump
vacuum.
Yield: 136 g of hygroscopic hydrochloride; melting point
(micro-Kofler): 125.degree.-127.degree. C.
2-(Methyl(2-nitrobenzyl)amino-1-(4-fluorophenyl)ethanol
##STR36##
140 g (0.413 mol) of
2-(methyl-(2-nitrobenzyl)-amino)-1-(4-fluorophenyl)ethanone are
dissolved in 82.8 ml of MeOH, the solution is cooled to 4.degree.
C. and a solution of 37.83 g (0.657 mol) of sodium borohydride in
270 ml of 0.1N NaOH is added dropwise in the course of 2 hours,
with stirring. The reaction mixture is stirred at room temperature
for 1 hour. It is concentrated on a rotary evaporator and the
residue is extracted with ethyl acetate. The organic phase is dried
over Na.sub.2 SO.sub.4 and the solvent is stripped off. The oily
residue is freed from traces of solvent under an oil pump
vacuum.
Yield: 124.5 g (99%).
2-(Methyl-(2-nitrobenzyl)amino)-1-(4-fluorophenyl)ethanone
##STR37##
135.8 g (0.67 mol) of methyl-(2-nitrobenzyl)-amine and 187.5 ml
(1.339 mols) of triethylamine are dissolved in 1.87 liters of
ethanol at room temperature, with stirring, and 148 g (0.682 mol)
of 2-bromo-1-(4-fluorophenyl)ethanone are then added in portions.
The reaction mixture is stirred for 3 hours. The solvent is then
stripped off on a rotary evaporator and the residue is dissolved in
1.3 liters of toluene. The toluene phase is washed several times
with H.sub.2 O and dried over Na.sub.2 SO.sub.4, and HCl/diethyl
ether is added. The glutinous precipitate is separated from the
toluene by decanting and crystallized with acetone. The colorless
precipitate is filtered off with suction and dried.
Yield: 158.5 g (70%); melting point (Mettler FP61): 171.9.degree.
C.
8-Methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]-indole-2,3-dione
##STR38##
17.5 g (0.0566 mol) of
N-methyl-4-phenyl-8-(hydroxyiminoacetylamino)isoquinoline were
added in small portions to 43.75 ml of concentrated H.sub.2
SO.sub.4 at 45.degree. C. and the mixture was warmed at 45.degree.
C. for 75 minutes. It was cooled to room temperature and poured
onto 450 g of ice. A pH of 6.8 was then established with 2N NaOH.
The precipitate which had separated out was filtered off with
suction and washed with water. After drying, 15.3 g (92.5% of
theory) of orange-colored crude product are obtained. (Melting
point of the pure product=about 188.degree. C., decomposition).
Preparation of the starting compound:
N-Methyl-4-phenyl-8-(hydroxyiminoacetylamino)isoquinoline
##STR39##
A solution of 10.75 g (0.0345 mol) of
N-methyl-4-phenyl-8-amino-isoquinoline hydrochloride in 22 ml of
H.sub.2 O was added to 6.23 g (0.0376 mol) of chloral hydrate in 86
ml of water. After 5 minutes, 42.5 g of Na.sub.2 SO.sub.4 and a
solution of 7.6 g (0.109 mol) of hydroxylamine hydrochloride in 36
ml of H.sub.2 O were added. The reaction mixture was warmed to
106.degree. C. (internal temperature) in the course of 40 minutes.
After 2 minutes, the mixture was cooled rapidly to 18.degree. C.
with ice/H.sub.2 O. 200 ml of methanol were added to the reaction
mixture and a pH of 7.6 was established with 2N NaOH. The
precipitate which had separated out was filtered off with suction
and washed thoroughly with H.sub.2 O. After drying, 9.7 g (90.2% of
theory) of crude product of melting point 151.3.degree. C. (Mettler
FP 61) were obtained.
EXAMPLE 2
8-Methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]-indole
##STR40##
20 g (0.524 mol) of LiAlH.sub.4 are suspended in 400 ml of absolute
diethyl ether at room temperature, with stirring, while flushing
with nitrogen and in the absence of moisture. 550 ml of absolute
tetrahydrofuran are then added, followed by 34 g (0.116 mol) of
8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole-2,3-dione
in portions. The reaction mixture is subsequently stirred at room
temperature for 31/2 hours. To dissociate the reaction complex, a
solution of 42 ml of H.sub.2 O in 160 ml of tetrahydrofuran is
added dropwise, with cooling. The inorganic solid is filtered off
and the filtrate is freed from the solvent on a rotary evaporator.
The residue is chromatographed on silica gel 60 with an eluent
mixture of: ethyl acetate and 8.3% of MeOH. The pure substance is
dried in a desiccator over P.sub.2 O.sub.5 at 60.degree. C. under a
water pump vacuum.
Yield: 9.1 g (30%); melting point (Mettler FP61): 157.9.degree.
C.
The following compound was prepared analogously:
8-Methyl-6-(4-fluorophenyl)-6,7,8,9-tetrahydro-1H-pyrido-[4,3-g]indole
##STR41##
Yield: 44% of theory; melting point (Mettler FP 61): 205.5.degree.
C.
Preparation of a salt with maleic acid
2.0 g (0.00713 mol) of
8-methyl-6-(4-fluorophenyl)-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole
are suspended in 10 ml of ethanol, and a solution of 0.91 g
(0.00784 mol) of maleic acid in 10 ml of ethanol is added, with
stirring. The reaction mixture is kept at room temperature for 1
hour. The crystalline product is filtered off with suction, washed
with ethanol/ether and dried in a desiccator at 95.degree. C. over
P.sub.2 O.sub.5 under a water pump vacuum.
Yield. 2.4 g (85%); melting point (Mettler FP 61): 170.5.degree.
C.
EXAMPLE 3
8-Methyl-6-phenyl-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3-g]-indole
##STR42##
12.5 ml (0.131 mol) of 10.5N hydrochloric acid are added dropwise
to a mixture of 26 g (0.1 mol) of
8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole and
29.2 g (0.4 mol) of trimethylaminoborane in 150 ml of absolute
dioxane at a temperature of 16.degree. C., with stirring and in the
absence of moisture. The mixture is then heated under reflux for 30
minutes and cooled to room temperature, 50 ml (0.3 mol) of 6N HCl
are added and the mixture is heated under reflux once more for 15
minutes. After cooling to room temperature, 600 ml of H.sub.2 O are
added to the reaction mixture, the mixture is filtered over
kieselguhr and, after addition of a further 600 ml of H.sub.2 O,
the filtrate is brought to pH 9 with 20% strength NaOH. The aqueous
phase is now extracted several times with CH.sub.2 Cl.sub.2 and,
after drying over Na.sub. 2 SO.sub.4, the solvent is distilled off
on a rotary evaporator. The oily residue is chromatographed on
silica gel (silica gel 60 from E. Merck, Darmstadt) using ethyl
acetate and MeOH (20:7) as the eluent.
Yield: 29.5 g (62.5%); melting point (Mettler FP 61): 125.1.degree.
C.
The following compound was prepared analogously to Example 3:
8-Methyl-6-(4-fluorophenyl)-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3-g]indole
##STR43##
The crude product was chromatographed on silica gel (silica gel 60
from E. Merck, Darmstadt) using an eluent mixture of ethyl acetate
and MeOH (2:1).
Yield: 3.0 g (43%); melting point (Mettler FP 61): 137.6.degree.
C.
Preparation of the hydrochloride ##STR44##
The base is converted into the hydrochloride with ethereal
hydrochloric acid.
Melting point (Mettler FP 61): 176.8.degree. C.
EXAMPLE 4
1,8-Dimethyl-6-(fluorophenyl)-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3-g]indole
##STR45##
2.3 g (0.00814 mol) of
8-methyl-6-(fluorophenyl)-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3-g]indole
are dissolved in 20 ml of MeOH, and 0.977 g (0.0163 mol) of acetic
acid and 0.791 ml (0.00976 mol) of formalin are added at room
temperature, with stirring. The reaction mixture is subsequently
stirred for 1 hour and 1.53 g (0.0244 mol) of sodium
cyanoborohydride are then added in several portions. In order to
bring the reaction to completion, the mixture is subsequently
stirred at room temperature for 1.5 hours. The solvent is then
stripped off on a rotary evaporator, H.sub.2 O is added to the
residue and the mixture is rendered alkaline with 1N NaOH. The
aqueous phase is extracted with CH.sub.2 Cl.sub.2 and dried over
NaSO.sub.4 and the solvent is evaporated off on a rotary
evaporator. The oily residue is chromatographed on silica gel
(silica gel 60 from E. Merck, Darmstadt) using an eluent mixture
of: CH.sub.2 Cl.sub.2 /MeOH (2.5:0.15). The product is dried in the
absence of light in a desiccator over P.sub.2 O.sub.5 at 10.sup.-2
bar.
Yield: 1.8 g of a syrupy product.
Preparation of the hydrochloride ##STR46##
The base is converted into the hydrochloride with ethereal
hydrochloric acid.
Melting point (Mettler FP 61): 188.8.degree. C. (with
decomposition)
EXAMPLE 5
1-(2-Pyrrolin-1-yl)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3-g
]indole ##STR47##
A solution of 1.9 ml (0.02 mol) of phosphorus oxychloride in 6 ml
of toluene is added dropwise to a solution of 3.4 g (0.04 mol) of
pyrrolid-2-one in 8 ml of toluene at a temperature between
2.degree. and 0.degree. C., with stirring and cooling. The mixture
is stirred at room temperature for 11/2 hours and left to stand
overnight. A solution of 5.2 g (0.02 mol) of
8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3-g]indole in
10 ml of toluene and 20 ml of CH.sub.2 Cl.sub.2 is then added. The
CH.sub.2 Cl.sub.2 is distilled off and the reaction mixture is
stirred at a temperature between 75.degree. and 80.degree. C. for 8
hours, with stirring. The solid which has precipitated is filtered
off with suction, and 2N NaOH and H.sub.2 O are added in order to
convert it into the free base. The aqueous phase is extracted with
CH.sub.2 Cl.sub.2, the CH.sub.2 Cl.sub.2 phase is dried and the
solvent is removed. The residue is chromatographed on silica gel 60
from E. Merck, Darmstadt) using an eluent mixture of CH.sub.2
Cl.sub.2 /MeOH (2:1), and on aluminum oxide (aluminum oxide 90 from
E. Merck, Darmstadt) using an eluent mixture of CH.sub.2 Cl.sub.2
and MeOH (20:0.25). The product is dried in a desiccator over
P.sub.2 O.sub.5 under a water pump vacuum.
Yield: 3.5 g (52.8%); melting point (Mettler FP 61): 57.9.degree.
C.
EXAMPLE 6
3-(1-Piperidinylmethyl)-6-phenyl-8-methyl-2,3,6,7,8,9-hexahydro-1H-pyrido[4
,3-g]indole ##STR48##
An ice-cooled solution of 1.51 ml (0.01524 mol) of piperidine and
1.14 ml of H.sub.2 O in 4.6 ml of acetic acid is added, together
with 1.14 ml (0.014 mol) of formalin, all at once, to 2.0 g
(0.00762 mol) of
8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole, with
stirring and while flushing with nitrogen. The mixture is then
rendered alkaline with 2N NaOH and extracted with CH.sub.2
Cl.sub.2. The CH.sub.2 Cl.sub.2 phase is dried over Na.sub.2
SO.sub.4 and the solvent is stripped off on a rotary evaporator.
The residue is chromatographed on silica gel (silica gel 60 from e.
Merck, Darmstadt) using an eluent mixture of CH.sub.2 Cl.sub.2
/MeOH/N(C.sub.2 H.sub.5).sub.3 (15:6:0.5). The product is dried in
a desiccator over P.sub.2 O.sub.5 under a water pump vacuum.
Yield: 3.1 g (89.6%); melting point (Mettler FP 61): 80.4.degree.
C.
Preparation of the hydrochloride ##STR49##
The base is converted into the hydrochloride in MeOH with 1N
aqueous HCl. After the solvent has been removed, the product is
dried in a desiccator over NaOH under a water pump vacuum at
95.degree. C.
Yield: 3.3 g (91.5%); melting point (Mettler FP 61): 212.8.degree.
C.
The following compounds were prepared analogously to Example 6:
3-Dimethylaminomethyl-8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]
indole ##STR50##
Yield: 78% of theory; melting point (Mettler FP 61): 80.9.degree.
C.
Preparation of the hydrochloride ##STR51##
The hydrochloride was obtained in MeOH with 1N aqueous HCl. Melting
point (Mettler FP 61): 203.degree. C.
3-(4-Morpholinylmethyl)-8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-
g]indole ##STR52##
The crude product was chromatographed on silica gel (silica gel 60
from E. Merck, Darmstadt) using an eluent mixture of CH.sub.2
Cl.sub.2 /MeOH/N(C.sub.2 H.sub.5).sub.3 (15:6:0.5), and the
substance was dried in a desiccator.
Yield: 97.5% of theory; melting point (Mettler FP 61): 77.3.degree.
C.
Preparation of the hydrochloride ##STR53##
The hydrochloride was prepared in MeOH with 1N aqueous HCl. Melting
point (Mettler FP 61): 257.degree. C.
EXAMPLE 7
3-Methylaminoethyl-8-methyl-6phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indo
le ##STR54##
4.9 g (0.129 mol) of LiAlH.sub.4 are initially introduced into 69.5
ml of absolute tetrahydrofuran, nitrogen is passed over and a
solution of 11.3 g (0.0325 mol) of
3-(8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]-indolyl)-2-oxo-ac
etic acid methylamide in 50 ml of absolute tetrahydrofuran is added
dropwise in the course of 15 minutes at room temperature, with
stirring and in the absence of moisture. The mixture is then heated
at the reflux temperature for 12 hours. A solution of 10 ml of
H.sub.2 O in 40 ml of tetrahydrofuran is then added dropwise to the
reaction mixture, with cooling and stirring. The inorganic content
is filtered off with suction and the residue on the filter is
washed thoroughly with CH.sub.2 Cl.sub.2. The filtrate is then
concentrated on a rotary evaporator and the residue is
chromatographed on silica gel (silica gel 60 from E. Merck,
Darmstadt) over a column with an eluent mixture of CH.sub.2
Cl.sub.2 /MeOH/N(C.sub.2 H.sub.5 ).sub.3 (15:10:0.5).
Yield: 3.9 g (37%).
Preparation of the hydrochloride ##STR55##
To prepare the hydrochloride, the base is dissolved in CH.sub.2
Cl.sub.2 and ethereal hydrochloric acid is added to the solution.
The solvent is stripped off and the residue is triturated with
ether. The HCl salt is dried over NaOH at 70.degree. C. under a
water pump vacuum.
Melting point (Mettler FP 61): 167.4.degree. C.
The following compound was prepared analogously:
3-(Isopropylaminoethyl)-8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-
g]indole ##STR56##
The crude product was chromatographed on silica gel (silica gel 60
from E. Merck, Darmstadt) using an eluent mixture of: CH.sub.2
Cl.sub.2 /MeOH/N(C.sub.2 H.sub.5).sub.3 (15:6:0.5). The substance
was then dried in a desiccator over P.sub.2 O.sub.5 under a water
pump vacuum.
Yield: 65% of theory.
Preparation of the hydrochloride ##STR57##
The hydrochloride was obtained as described above.
Melting point (Mettler FP 61): 223.5.degree. C.
Preparation of the starting compounds
3-(8-Methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]-indol-yl)-2-oxo-ac
etic acid methylamide ##STR58##
7.92 ml (0.0918 mol) of oxalyl chloride are added to 5.5 g (0.0397
mol) of K.sub.2 CO.sub.3 in 78.5 ml of absolute dioxane and the
mixture is cooled to 0.degree. C. in the absence of moisture. A
solution of
8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole in 196
ml of absolute dioxane is now added dropwise in the course of 30
minutes, with stirring, and the mixture is subsequently stirred at
room temperature for 16 hours in order to bring the reaction to
completion. 10.9 g (0.0791 mol) of K.sub.2 co.sub.3 are then added,
a solution of 12.1 g (0.389 mol) of anhydrous methylamine in 100 ml
of absolute dioxane is subsequently added dropwise and the mixture
is allowed to after-react for 21/2 hours. The solvent is stripped
off on a rotary evaporator; 150 ml of H.sub.2 O are added to the
residue and the aqueous phase is extracted by shaking with 150 ml
of diethyl ether. The insoluble substance content is filtered off,
washed with 50 ml of CH.sub.2 Cl.sub.2 and dried over P.sub.2
O.sub.5 at 60.degree. C. under a water pump vacuum.
Yield: 10.1 g (74%); melting point (Mettler FP 61): 224.7.degree.
C.
The following compound was obtained by an analogous route:
3-(8-Methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]-indol-yl)-2-oxo-ac
etic acid isopropylamide ##STR59##
The crude product was chromatographed on silica gel (silica gel 60
from E. Merck, Darmstadt) using an eluent mixture of ethyl acetate
and MeOH (9:1). The substance was then dried over P.sub.2 O.sub.5
under a water pump vacuum.
Yield: 65% of theory.
Preparation of the hydrochloride ##STR60##
The hydrochloride was prepared as described for the salts of
Example 7.
Melting point (Mettler FP 61): 257.6.degree. C.
EXAMPLE 8
3-(Isopropylaminoethyl)-8-methyl-6-phenyl-2,3,6,7,8,9-hexahydro-1H-pyrido[4
,3-g]indole ##STR61##
2.1 g (0.00604 mol) of
3-(isopropylaminoethyl)-8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3
-g]-indole are dissolved in 25 ml (0.3275 mol) of trifluoroacetic
acid, with stirring and in the absence of moisture, and a solution
of 1.76 g (0.0241 mol) of trimethylaminoborane in 10 ml of
tetrahydrofuran is then added dropwise at a temperature of
0.degree.-+2.degree. C. The mixture is subsequently stirred at
0.degree. C. for 1 hour, a solution of 1.76 g (0.0241 mol) of
trimethylamonoborane in 10 ml of tetrahydrofuran is then again
added and the mixture is subsequently stirred for 2.5 hours. 150 ml
of H.sub.2 O are now added to the reaction mixture, the mixture is
brought to pH 13 with NaOH and the oily product which deposits is
extracted with CH.sub.2 Cl.sub.2. The CH.sub.2 Cl.sub.2 phase is
washed with H.sub.2 O, dried over Na.sub.2 SO.sub.4 and then freed
from the solvent on a rotary evaporator. The residue is
chromatographed twice on silica gel (silica gel 60 from E. Merck,
Darmstadt). Eluent: initially CH.sub.2 Cl.sub.2 /MeOH/N(C.sub.2
H.sub.5).sub.3 (15:4:0.25), then diethyl ether/MeOH/N(C.sub.2
H.sub.5).sub.3 (15:3:0.25).
Yield: 1.3 g of a colorless syrupy substance (61.5%).
Preparation of the hydrochloride ##STR62##
The hydrochloride was obtained as described in Example 7.
Melting point (Mettler FP 61): 223.degree. C.
EXAMPLE 9
3,7-Dimethyl-9-phenyl-1,2,3,4,6,7,8,9-octahydro-5H-dipyrido[4,3-g:3',4'-b]i
ndole ##STR63##
0.15 ml of 1N HCl (0.00015 mol) is added to 0.8 g (0.0025 mol) of
3-(methylaminoethyl)-8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]
indole, 0.23 ml (0.0028 mol) of 40% strength formalin solution and
1.5 ml of 0.1N HCl (0.00015 mol) and the mixture is then stirred at
room temperature for 2 hours. The crystalline substance which forms
is dissolved with 2 ml of ethyl alcohol and the solution is left to
stand overnight. The solvent is stripped off on a rotary
evaporator, aqueous KHCO.sub.3 solution is added to the residue and
the aqueous phase is extracted with CH.sub.2 Cl.sub.2. The CH.sub.2
Cl phase is dried over Na.sub.2 SO.sub.4 and the solvent is
stripped off on a rotary evaporator. The residue is separated on
silica gel (silica gel 60 from E. Merck, Darmstadt) over a column
with the eluent ethyl acetate/MeOH/(N(C.sub.2 H.sub.5).sub.3
(9:3.5:0.25).
Yield: 0.6 g (73%).
Preparation of the hydrochloride ##STR64##
The hydrochloride of the base was obtained analogously to Example
7.
Melting point (micro-Kofler): 236.degree.-237.degree. C.
EXAMPLE 10
2-(N-Piperidino)-3-ethylenedioxy-6-phenyl-8-methyl-6,7,8,9-tetrahydro-3H-py
rido[4,3-g]indole ##STR65##
3,1 g (0.00879 mol) of
2-thiono-3-ethylenedioxy-6-phenyl-8-methyl-2,3,6,7,8,9-hexahydro-1H-pyrido
[4,3-g]-indole are dissolved in 42.5 ml (0.429 mol) of piperidine,
with stirring, and the mixture is warmed at 110.degree. C. for 1
hour, in the absence of moisture and while flushing with nitrogen.
The excess piperidine is distilled off on a rotary evaporator, the
residue is dissolved in CH.sub.2 Cl.sub.2 and the CH.sub.2 Cl.sub.2
phase is extracted 3 times with H.sub.2 O. The organic phase is
dried over Na.sub.2 SO.sub.4 and the solvent is stripped off on a
rotary evaporator. The residue is chromatographed on aluminum oxide
(aluminum oxide 90 from E. Merck, Darmstadt) using an eluent
mixture of methylene chloride/methanol (20;0.05). The substance is
dried over P.sub.2 O.sub.5 under a water pump vacuum.
Yield: 1.1 g (24.5%); melting point (micro-Kofler):
215.degree.-216.degree. C.
The following compound was obtained analogously to Example 10:
2-Butylimino-3-ethylenedioxy-6-phenyl-8-methyl-2,3,6,7,8,9-hexahydro-1H-pyr
ido[4,3-g]indole ##STR66##
The crude product was chromatographed on silica gel (silica gel 60
from E. Merck, Darmstadt) using an eluent mixture of ethyl acetate
and methanol (9:1). The pure substance was dried over P.sub.2
O.sub.5 at 60.degree. C. under a water pump vacuum.
Yield: 49% of theory; melting point (Mettler FP 61): 87.3.degree.
C.
Preparation of the starting substances
2-Thiono-3-ethylenedioxy-6-phenyl-8-methyl-2,3,6,7,8,9-hexahydro-1H-pyrido-
[4,3-g]indole ##STR67##
A suspension of 1.68 g (0.005 mol) of
2-oxo-3-ethylenedioxy-6-phenyl-8-methyl-2,3,6,7,8,9-hexahydro-1H-pyrido[4,
3-g]indole and 1.0 g (0.0025 mol) of Lawessson's reagent in 10 ml
of absolute toluene is heated at the reflux temperature for 1 hour,
in the absence of moisture and with stirring. The reaction mixture
is then freed from the solvent on a rotary evaporator and the
residue is chromatographed on silica gel (silica gel 60 from E.
Merck, Darmstadt) using an eluent mixture of CH.sub.2 Cl.sub.2 and
MeOH (20:1). The substance is dried over P.sub.2 O.sub.5 under a
water pump vacuum.
Yield: 0.85 g (49%).
2-Oxo-3-ethylenedioxy-6-phenyl-8-methyl-2,3,6,7,8,9-hexahydro-1H-pyrido[4,3
-g]indole ##STR68##
100 ml of dichloroethane are added to 20.6 g (0.0624 mol) of
8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole-2,3-dione,
21 ml (0.374 mol) of ethylene glycol and 0.336 g (0.00176 mol) of
toluene-4-sulphonic acid monohydrate, with stirring, and the
mixture is heated under reflux for 3.5 hours, using a water
separator. Ice is added to the reaction mixture and the mixture is
brought to pH 6.8 with aqueous KHCO.sub.3 solution. The mixture is
extracted with CH.sub.2 Cl.sub.2, the CH.sub.2 Cl.sub.2 phase is
washed with H.sub.2 O and dried over Na.sub.2 SO.sub.4 and the
solvent is stripped off in a rotary evaporator. The residue is
chromatographed on Al.sub.2 O.sub.3 (aluminum oxide from E. Merck,
Darmstadt) using an eluent mixture of ethyl acetate and MeOH
(20:0.2). After trituration with ethyl acetate/petroleum ether, the
substance becomes crystalline. It is dried over P.sub.2 O.sub.5 at
80.degree. C. in vacuo.
Yield: 12.5 g (59.5%);
melting point (Mettler FP 61): 221.2.degree. C.
It is understood that the specification and examples are
illustrative but not limitative of the present invention and that
other embodiments within the spirit and scope of the invention will
suggest themselves to those skilled in the art.
* * * * *